We are investigating whether Apolipoprotein E (ApoE) genotype is a risk factor for the early onset of Alzheimer 's Disease (AD) in adults with Down syndrome (DS). We have determined genotypes in 94 individuals, and have found a highly significant absence of e4 homozygotes. We are investigating whether this may be due to reduced survival of e4 homozygous individuals. Individuals with Down's Syndrome (DS) develop the neuropathology of Alzheimer's Disease (AD) by age 40. One of the Apolipoprotein E (ApoE) alleles, e4, is a risk factor for the development of AD in the general population: the e4 allele is found with an increased frequency in late- onset familial and sporadic AD populations. We determined ApoE genotypes in 94 adults with DS aged 30 or over. Genotypes were as follows: e3/3 n--59; e2/3 n7--8; e2/2 n--I; e2/4 n=5; e3/4 n--21. The allele frequency of e4 in our sample is 13.8%. We did not identify any e4/4 individuals; this was unexpected from our e4 allele frequency (p=O. 011). Other studies have been published with individual genotypes in adults with DS, finding a range of e4 allele frequencies but no e4 homozygotes. Even applying the lowest published allele frequency (1.25%) in our study, it is unexpected that no e4 homozygotes were detected (p=O.O I 1); assuming a more typical allele frequency of 10%, this is highly unlikely (p<0.0001). Combining our study with all the above published studies (n--460 alleles, e4 allele frequency is 12%), it is even more unlikely that no e4 homozygotes have been detected (P<0.0001). The lack of e4 homozygotes in published samples with DS is intriguing, and as e4 frequencies in DS (10-14%, 95% confidence interval 3-26% ) are generally within the normal range (14%, 95% confidence interval 12-16%), this suggests reduced survival of e4 homozygotes. Simple possibilities include embryonic lethality or premature death, possibly from heart disease: the e4 allele has been associated with ischemic heart disease in several studies. To distinguish between these possibilities, we have collected a number of samples from newborn DS infants to determine ApoE allele frequencies.